title: HIF isoforms in the skin differentially regulate systemic arterial pressure.
abstract: Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1α and HIF-2α, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.
authors.affiliation: Departments of Physiology, Development and Neuroscience and Medicine, University of Cambridge CB2 3EG, Cambridge, United Kingdom.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.forename: Adam T
authors.initials: AT
authors.lastname: Boutin
authors.forename: Jung-Whan
authors.initials: JW
authors.lastname: Kim
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sterling
authors.forename: Manando
authors.initials: M
authors.lastname: Nakasaki
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.forename: Colin
authors.initials: C
authors.lastname: Jamora
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D062186:Arterial Pressure / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000098:blood supply* / Q000378:metabolism*; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001119:Arginase; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000099162:Endothelial PAS Domain-Containing Protein 1; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C544448:Arg1 protein, mouse; C481673:Arg2 protein, mouse
keywords: HIF-alpha; arginase; vascular tone